1. Technical Field
This document relates to methods and materials involved in treating mammals (e.g., humans) having a sexual dysfunction that is refractory to treatment with a phosphodiesterase V (PDE V) inhibitor. For example, this document relates to methods and compositions for treating a sexual dysfunction (e.g., erectile dysfunction) refractory to PDE V inhibition using an angiotensin-converting enzyme (ACE) inhibitor and/or an angiotensin II receptor blocker and a PDE V inhibitor.
2. Background Information
Nitric oxide (NO) is a lipophilic, free radical gas that has many physiological functions, such as mediating vasodilation. The endothelial isoform of nitric oxide synthase is a key source of NO in the cardiovascular system. NO that is generated by endothelial cells diffuses into adjacent smooth muscle cells where it binds to a heme moiety on guanylyl cyclase and activates the enzyme to produce cGMP from GTP. Increased cGMP activates cGMP-dependent protein kinase type Iα (PKGIα). One of the targets of PKGIα in smooth muscle is myosin light chain (MLC) phosphatase. Activation of MLC phosphatase leads to dephosphorylation of myosin light chains, thereby decreasing smooth muscle tension and causing vasodilation.
MLC phosphatase is a holoenzyme consisting of a catalytic subunit (PP1cδ), a myosin-targeting subunit (MYPT1), and a 20-kDa subunit of unknown function. The MYPT1 subunit has four major isoforms, which are produced by alternative RNA splicing of two different exons. Tissue-specific and developmentally regulated alternative splicing of a 123-bp central exon produces a 41-amino acid central insert. Alternative splicing of the 31-bp 3′-exon is responsible for expression of leucine zipper positive (LZ−) or leucine zipper negative (LZ−) MYPT1 isoforms. Specifically, exclusion of the 3′-exon shifts the reading frame of the MYPT1 transcript to encode a carboxy terminal LZ domain. The carboxy terminal LZ domain of the MYPT1 subunit is required for activation of MLC phosphatase by PKGIα.